ABSTRACT Opioid misuse, including prescription opioids, heroin and fentanyl, is epidemic in the United States and is associated with high morbidity and mortality. The current National Survey on Drug Use and Health estimates that at least 2.6 million people met criteria for an opioid use disorder (including prescription opioids and heroin). Opioid-related overdose deaths continue to climb with nearly 30,000 deaths reported in 2014. Toxicological evidence from post-mortem studies reveals that polypharmacy is a very common finding in opioid-related deaths, and it is especially common to find co-occurring substances with sedative properties. Despite the widespread acknowledgment that non-opioid sedatives may enhance the risk of death from an opioid overdose, few controlled data exist on the pharmacodynamic effects of opioids in combination with these agents and their co-prescription by providers is common. These studies aim to fill this critical knowledge gap by assessing agents with sedative properties that commonly are 1) prescribed with opioids (i.e., benzodiazepines, gabapentin), 2) abused in combination with opioids, and 3) found in combination at autopsy (benzodiazepines, alcohol and gabapentin). Three inpatient human laboratory studies will be conducted that employ rigorous controlled experimental procedures to characterize the pharmacological interaction between oxycodone when taken in combination with either alprazolam (Experiment 1), alcohol (Experiment 2) or gabapentin (Experiment 3). Individuals with appropriate recreational drug use histories, who are otherwise healthy, will be enrolled. An initial dose finding phase will precede each study to ensure subject safety and scientific rigor before proceeding to a robust randomized controlled design. The three studies will employ randomized, placebo-controlled, within-subject, double-blind crossover designs and will be conducted in a controlled hospital setting where appropriate medical supervision is available. Key safety outcomes, including expired CO2 and other respiratory function indices, pharmacodynamic measures related to abuse potential, and cognitive/psychomotor performance will be thoroughly examined over a range of doses for all drugs alone. Pharmacokinetic data (Exp. 1) will also be collected to assess the potential pharmacokinetic interaction as an underlying mechanism of action, and experimental analgesia/algesia data will be collected in Exp. 3 as gabapentin is commonly co-prescribed for pain relief with opioids. The analytic approach will include traditional statistics and modified isobolographic analyses to further elucidate the nature of the pharmacodynamic interactions. The findings from these studies may directly inform prescribing practices and inform clinical guidelines for physicians and other providers, regulatory decision-making, and may provide new information for targeted interventions to reduce the harms of polysubstance prescribing and misuse.